Pellet formulations of acid-labile benzimidazonle compounds

Abstract

They comprise insert granules of sugar/starch which are: initially coated with a non-alkaline active layer having the benzimidazole compound (omeprazole, lansoprazole, pantoprazole, rabeprazole, etc.), sodium and/potassium salts of acids of formula R—O—SO₃H wherein R is an alkyl radical of a (C₆-C₂₀)-fatty acid (preferably sodium lauryl sulfate), (C₆-C₂₀)-fatty acids (preferably oleic acid), sodium and/or potassium salts of (C₆-C₂₀)-fatty acids (preferably potassium oleate), sodium carboxymethyl starch and polyvinylpyrrolidone; secondly coated with a non-alkaline barrier layer having hydroxypropylmethylcellulose; and finally coated with an enteric layer. The preferred molar ratio (sodium lauryl sulfate):(oleic acid+potassium oleate) is between 4:1 and 6:1. All coatings are done with aqueous solutions, suspensions or dispersions at a relatively high temperature, and all dryings are done at a relatively low temperature and for a relatively short time. They are stable over time and useful for oral administration.

Description

[0001] The present invention relates to new pellet formulations for oral administration of known acid labile benzimidazole compounds, and to a preparation process thereof. BACKGROUND ART [0002] Benzimidazole compounds of formula (I), wherein R1 is selected from the group consisting of hydrogen, methoxy and difluoromethoxy; R2 is selected from the group consisting of methyl and methoxy; R3 is selected from the group consisting of methoxy, 2,2,2-trifluoroethoxy and 3-methoxypropoxy; R4 is selected from the group consisting of hydrogen and methyl are a group of pharmaceutical active ingredients known to be useful for the treatment of gastrointestinal diseases and / or disorders. This group include commercial pharmaceutical active substances such as omeprazole (wherein R1=R3=methoxy; R2=R4=methyl), lansoprazole (wherein R1=R4=hydrogen; R2=methyl; R3=2,2,2-trifluoroethoxy), pantoprazole (wherein R1=difluoromethoxy; R2=R3=methoxy; R4=hydrogen) and rabeprazole (wherein R1=R4=hydrogen; R2=met...

AI Technical Summary

Benefits of technology

[0023] The preparation process of the pellet formulations of the present invention allows a first active coating at a relatively high temperature of granules (from about 50° C. to about 70° C.), substantially higher than the temperature corresponding to processes known in the art (e.g. 40° C. in EP 237.200-A). It also allows drying at relatively low temperatures (25-35° C.) and/or for short times (20 min), all of which represent manufacturing advantages over other processes known in the art (e.g. 40° C. for 16 h in EP 237.200-A; 50° C. for 4 h in WO 0071121-A).

[0024] Throughout the descri

Problems solved by technology

It is well known that the benzimidazole compound has a poor stability over time.

In the solid state it is susceptible to moisture, light and heat, and in aqueous solution or suspension the stability decreases with decreasing pH.

As conventional enteric coatings are acidic, the need of protecting the pharmaceutical active ingredient from the enteric

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